The present invention demonstrates methods of regenerating new collagen-containing tissue, e.g., bone, connective tissue, cartilage, facia, ligaments, tendons and other collagen tissue of type I, II, or III that have collagen as an organic constituent, and also epithelium. More specifically, this invention relates to a treatment comprising the use of misoprostol, an analog of prostaglandin E.sub.1 for regenerating new collagen-containing tissues.
Loss of collagen can occur as a result of several mechanisms, e.g. genetic, enzyme degradation, or cell injury due to thermal, mechanical, chemical, and radiation (including UV light) traumas. This loss of collagen thins the skin, increases likelihood of injury and causes a delay in the healing response. At the present time no specific therapies exist to regenerate collagen after its breakdown, especially that associated with aging. In skin the attritional loss of collagen from breakdown and decreased synthesis of new collagen results in a thinning and the loss of structural integrity. The consequence of these changes is a looseness and wrinkling of the skin.
Recently, the discovery of natural products labeled as growth factors to promote growth and healing of connective and support tissues have been reported. These substances are usually proteins and appear to be ideal for inducing support and connective tissue repair, but in reality such factors are not practical as pharmaceutical agents. These proteins, like other proteins are not stable and break down upon storage. They also are not suitable for oral administration since they are digested and destroyed before entering the blood stream. Their administration as topical pharmaceutical agents is not possible. There then is only one route and that is parenteral but because they are proteins, they are recognized by the body as foreign. Thus, there is the constant danger of eliciting an immune response. This route does not necessarily target the right tissue and is more likely to affect many different cells throughout the body. The current invention uses topical application to areas of the body that require connective tissue repair and regeneration without oral or parenteral routes.
The present invention demonstrates new methods to regenerate connective and support tissues in humans and animals. These methods provide new treatment modalities useful in the treatment of connective tissue disorders which have occurred as the result of a deficiency in which the regenerative tissues of the skin and organs lack the ability to produce collagen in sufficient quantities to eradicate the existing disease state. Regeneration is the growth and differentiation of new cells and intercellular substances to form new tissues or parts. It consists of fibroplasia, endothelial proliferation, the deposition of interstitial ground substance and collagen, epithelial hyperplasia and the maturation of connective tissue. Bone and cementum are not replaced by existing bone or cementum, but from connective tissue, which is the precursor of both. Undifferentiated connective tissue cells develop into osteoblasts and cementoblasts which form bone and cementum. In periodontal tissues, regeneration is a microscopic activity which differs in degrees from clinically radiographically detectable restoration of destroyed periodontal tissues. Regeneration in most instances restores the continuity of diseased marginal gingiva and reestablishes a normal gingival sulcus at the same level on the root as the base of the pre-existing periodontal pocket. Reattachment is the re-embedding of new periodontal ligament fibers into new cementum and the attachment of gingival epithelium to tooth surface previously denuded by disease.
The present invention provides the use of misoprostal to produce new epithelium, bone, connective tissue, cartilage, fascia, ligaments, tendons and collagen tissues of type I, II, and III. The use of topical preparations of misoprostol cause an increase in fibroblastic activity in skin and mucous membranes. This results in the production of collagen type I. This can be measured quantitatively. The increased response to healing as a result of this treatment will result in thickening to the skin, lessening of the prominence of facial rhytids, improved skin turgor and elastic properties, accelerated healing of wounds and/or scars resulting from thermal, chemical, or mechanical etiologies, free graft (split or full thickness) survival enhancement, and increased healing of mucous membrane injuries with a decrease in pain associated with all of these conditions as a result of decreased inflammation, coupled with accelerated healing.
In summary, the method of the present invention provides a new treatment that accelerates healing for the patient, reduces trauma from surgeries that no longer need to be performed, and reduces cost to the patient. Also, in necessary surgeries such as gingival grafting, it accelerates healing of both the donor site and graft site. Using misoprostol with a local anesthetic such as dyclonine makes the surgical procedures almost painless. Also, a reduction of dry sockets after extractions is being found with the present procedure, thus almost eliminating them as a problem in the dental office. The advantage for the periodontal patient is that it eliminates much of the surgery if this process is used on early periodontal cases along with good oral hygiene and maintenance care.
The therapy disclosed herein using misoprostol as a topical application has shown dramatic results within as little as 3 to 5 days. Re-epithelialization occurs rapidly with the use of misoprostol when secondary infection is controlled. The usual course of treatment if signs of secondary infection occur is to dose with antibiotic and/or antifungals, in addition to misoprostol topically applied directly to the area.
The effect of chemotherapy and radiotherapy are similar. It is based on the ability to non-specifically destroy or retard the division of rapidly proliferating malignant cells with specific drugs or radiation. Normal cells with rapid turnover, such as oral mucosa or the alimentary canal, are also affected and may result in toxicity and complications. Approximately 20% of patients with cancer are treated with chemotherapy at some time during the course of their disease; also there are approximately 250,000 episodes of oral complications each year. These incidences are likely to increase with the use of more potent drugs and multimodality therapy combining radiation and new chemotherapy.
Control of secondary infections using antibiotics and/or antifungal agents in combination with the present misoprostol routine creates re-epithelialization and inflammation reduction within 3 to 5 days. The application is directly to the injured tissue by gels, ointments, creams or lotions with misoprostol as the active ingredient, preferably 4 to 5 times daily.
Misoprostol is an analog of prostaglandin E.sub.1 and is broken down by most tissues of the body to misoprostol acid, the active metabolyte. Misoprostol has been used in the past on a prescription basis as a gastric mucosa protectant and antiulcer agent. Its primary use is the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcers, and short term treatment of duodenal ulcers. In contrast, the present method demonstrates regeneration or a re-epithelialization of damaged tissues and reduced healing times.
Misoprostol may be administered alone or in combination with other pharmaceutically acceptable agents. Dosages of from not less than about 1 .mu.g per day to no more than about 5 mg per day of the individual compounds per se, or in combinations, are generally effective. In this regard, misoprostol is present in a composition in an amount from about 1 .mu.g to about 1 mg per gram of the composition. Various formulations for the compositions are provided herein. Such formulations may include gels, creams, lotions, ointments, and the like. The compositions and/or formulations may also include additional active ingredients if desired, such as local anesthetics.
The method disclosed herein provides a novel method for the regeneration of collagen-containing tissues. For example, epithelium, bone, connective tissue, cartilage, fascia, ligaments, tendons and other collagen tissues of type I, II or III that have collagen as an organic constituent may all be treated with misoprostol. It will be evident that the method will find ready application for the prevention or treatment of damaged tissues other than those named, for example dermatological tissues, in which faster wound healing is desired. For example, the treatment in the present invention may also find ready application in severe burn and skin regeneration, skin grafts, pressure sores, diabetic ulcers, fissures, post surgery scar reduction, dry socket, ulcerative colitis, rectal and anal fissures. This treatment also improves healing from dermatological surgery, and any surgery involving epithelial tissue.
The present method has the distinct unexpected advantage that it will provide a highly effective treatment for regenerating, not merely preserving or protecting, collagen-containing tissues, and all epithelial tissues, and at the same time this compound advantageously will not produce unwanted systemic or local side effects even if the compound is administered continuously on a daily basis, as long as the appropriate compound dosages are used. It, of course, must be understood that the dosage levels will be adjusted dependent on the response of the subject and the degree of damage to the tissues as monitored by methods known to those skilled in the art.